tbuckley/cabot-search huggingface dataset:
Ribosomal DNA Instability as a Potential Cause of Karyotype Evolution
Authors: Duojia Li, Dhyey Gandhi, Tomohiro Kumon, Yukiko M Yamashita
Journal: Molecular Biology and Evolution (2022)

Abstract Karyotype refers to the configuration of the genome into a set of chromosomes. The karyotype difference between species is expected to impede various biological processes, such as chromosome segregation and meiotic chromosome pairing, potentially contributing to incompatibility. Karyotypes can rapidly change between closely related species and even among populations of the same species. However, the forces driving karyotype evolution are poorly understood. Here we describe a unique karyotype of a Drosophila melanogaster strain isolated from the Seychelles archipelago. This strain has lost the ribosomal DNA (rDNA) locus on the X chromosome. Because the Y chromosome is the only other rDNA-bearing chromosome, all females carry at least one Y chromosome as the source of rDNA. Interestingly, we found that the strain also carries a truncated Y chromosome (YS) that is stably maintained in the population despite its inability to support male fertility. Our modeling and cytological analysis suggest that the Y chromosome has a larger negative impact on female fitness than the YS chromosome. Moreover, we generated an independent strain that lacks X rDNA and has a karyotype of XXY females and XY males. This strain quickly evolved multiple karyotypes: two new truncated Y chromosomes (similar to YS), as well as two independent X chromosome fusions that contain the Y-derived rDNA fragment, eliminating females’ dependence on the Y chromosome. Considering that Robertsonian fusions frequently occur at rDNA loci in humans, we propose that rDNA loci instability may be one of driving forces of karyotype evolution.
Temperature-dependent Small RNA Expression Depends on Wild Genetic Backgrounds of <i>Caenorhabditis briggsae</i>
Authors: Daniel D Fusca, Eesha Sharma, Jörg G Weiss, Julie M Claycomb, Asher D Cutter
Journal: Molecular Biology and Evolution (2022)

Geographically distinct populations can adapt to the temperature conditions of their local environment, leading to temperature-dependent fitness differences between populations. Consistent with local adaptation, phylogeographically distinct Caenorhabditis briggsae nematodes show distinct fitness responses to temperature. The genetic mechanisms underlying local adaptation, however, remain unresolved. To investigate the potential role of small noncoding RNAs in genotype-specific responses to temperature, we quantified small RNA expression using high-throughput sequencing of C. briggsae nematodes from tropical and temperate strain genotypes reared under three temperature conditions (14 °C, 20 °C, and 30 C). Strains representing both tropical and temperate regions showed significantly lower expression of PIWI-interacting RNAs (piRNAs) at high temperatures, primarily mapping to a large ∼7 Mb long piRNA cluster on chromosome IV. We also documented decreased expression of 22G-RNAs antisense to protein-coding genes and other genomic features at high rearing temperatures for the thermally-intolerant temperate strain genotype, but not for the tropical strain genotype. Reduced 22G-RNA expression was widespread along chromosomes and among feature types, indicative of a genome-wide response. Targets of the EGO-1/CSR-1 22G-RNA pathway were most strongly impacted compared with other 22G-RNA pathways, implicating the CSR-1 Argonaute and its RNA-dependent RNA polymerase EGO-1 in the genotype-dependent modulation of C. briggsae 22G-RNAs under chronic thermal stress. Our work suggests that gene regulation via small RNAs may be an important contributor to the evolution of local adaptations.
Miniature Inverted-repeat Transposable Elements Drive Rapid MicroRNA Diversification in Angiosperms
Authors: Zhonglong Guo, Zheng Kuang, Yihan Tao, Haotian Wang, Miaomiao Wan, Chen Hao, Fei Shen, Xiaozeng Yang, Lei Li
Journal: Molecular Biology and Evolution (2022)

MicroRNAs (miRNAs) are fast evolving endogenous small RNAs that regulate organism function and behavior in both animals and plants. Although models for de novo miRNA biogenesis have been proposed, the genomic mechanisms driving swift diversification of the miRNA repertoires in plants remain elusive. Here, by comprehensively analyzing 21 phylogenetically representative plant species, ranging from green algae to angiosperms, we systematically identified de novo miRNA events associated with 8,649 miRNA loci. We found that 399 (4.6%), 466 (5.4%), and 1,402 (16.2%) miRNAs were derived from inverted gene duplication events, long terminal repeats of retrotransposons, and miniature inverted-repeat transposable elements (MITEs), respectively. Among the miRNAs of these origins, MITEs, especially those belonging to the Mutator, Tc1/Mariner, and PIF/Harbinger superfamilies, were the predominant genomic source for de novo miRNAs in the 15 examined angiosperms but not in the six non-angiosperms. Our data further illustrated a transposition-transcription process by which MITEs are converted into new miRNAs (termed MITE-miRNAs) whereby properly sized MITEs are transcribed and therefore become potential substrates for the miRNA processing machinery by transposing into introns of active genes. By analyzing the 58,038 putative target genes for the 8,095 miRNAs, we found that the target genes of MITE-miRNAs were preferentially associated with response to environmental stimuli such as temperature, suggesting that MITE-miRNAs are pertinent to plant adaptation. Collectively, these findings demonstrate that molecular conversion of MITEs is a genomic mechanism leading to rapid and continuous changes to the miRNA repertoires in angiosperm.
Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma
Authors: Naser Ansari-Pour, Mehmet Samur, Erin Flynt, Sarah Gooding, Fadi Towfic, Nicholas Stong, Maria Ortiz Estevez, Konstantinos Mavrommatis, Brian Walker, Gareth Morgan, Nikhil Munshi, Herve Avet-Loiseau, Anjan Thakurta
Journal: Blood (2022)

Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.
Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes
Authors: Monika I. Linder, Yoko Mizoguchi, Sebastian Hesse, Gergely Csaba, Megumi Tatematsu, Marcin Łyszkiewicz, Natalia Ziȩtara, Tim Jeske, Maximilian Hastreiter, Meino Rohlfs, Yanshan Liu, Piotr Grabowski, Kaarin Ahomaa, Daniela Maier-Begandt, Marko Schwestka, Vahid Pazhakh, Abdulsalam I. Isiaku, Brenda Briones Miranda, Piers Blombery, Megumu K. Saito, Ejona Rusha, Zahra Alizadeh, Zahra Pourpak, Masao Kobayashi, Nima Rezaei, Ekrem Unal, Fabian Hauck, Micha Drukker, Barbara Walzog, Juri Rappsilber, Ralf Zimmer, Graham J. Lieschke, Christoph Klein
Journal: Blood (2022)

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.
DaBlaCa-13 Study: Oncological Outcome of Short-Term, Intensive Chemoresection With Mitomycin in Nonmuscle Invasive Bladder Cancer: Primary Outcome of a Randomized Controlled Trial
Authors: Maria S. Lindgren, Erik Hansen, Nessn Azawi, Anna M. Nielsen, Lars Dyrskjøt, Jørgen B. Jensen
Journal: Journal of Clinical Oncology (2022)

This study aimed to assess long-term follow-up after chemoresection with mitomycin (MMC), a nonsurgical treatment modality for recurrent nonmuscle invasive bladder cancer (NMIBC). At the time of recurrence, chemoresection has previously been shown to reduce the number of patients requiring a procedure (transurethral resection of bladder tumors [TURBT] or office biopsy) by more than 50%. This study investigated the number of patients requiring a procedure during initial treatment and 2-year follow-up in patients treated with short-term, intensive chemoresection with MMC compared with patients undergoing standard surgical treatment of recurrent NMIBC.A randomized, controlled trial was conducted in two urological departments in Denmark from January 2018 to August 2021. In total, 120 patients with a history of Ta low- or high-grade NMIBC were included upon recurrence. The intervention group received intravesical MMC (40 mg/40 mL) three times a week for 2 weeks and TURBT or office biopsy only if the response was incomplete. The control group received TURBT or office biopsy and 6 weekly adjuvant instillations. The primary outcome was the number of patients undergoing a procedure within 2 years from inclusion, which was compared between groups using the chi-squared test. Recurrence-free survival was analyzed using the Kaplan-Meier method.Significantly fewer patients were in need of a procedure in the intervention group than in the control group: 71% (95% CI, 57 to 81) and 100% (95% CI, 94 to 100), P < .001. The 12-month recurrence-free survival was 36% (95% CI, 24 to 50) and 43% (95% CI, 30 to 56) in the intervention and control groups, respectively (P = .5).Short-term intensive chemoresection is an effective treatment strategy for recurrent NMIBC that leads to a reduced number of required procedures without compromising long-term oncological safety.
CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality
Authors: Carlo Sorrentino, Luigi D’Antonio, Stefania Livia Ciummo, Cristiano Fieni, Lorena Landuzzi, Francesca Ruzzi, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Pier Luigi Lollini, Emma Di Carlo
Journal: Journal of Hematology & Oncology (2022)

Metastatic prostate cancer (PC) is a leading cause of cancer death in men worldwide. Targeting of the culprits of disease progression is an unmet need. Interleukin (IL)-30 promotes PC onset and development, but whether it can be a suitable therapeutic target remains to be investigated. Here, we shed light on the relationship between IL30 and canonical PC driver genes and explored the anti-tumor potential of CRISPR/Cas9-mediated deletion of IL30.PC cell production of, and response to, IL30 was tested by flow cytometry, immunoelectron microscopy, invasion and migration assays and PCR arrays. Syngeneic and xenograft models were used to investigate the effects of IL30, and its deletion by CRISPR/Cas9 genome editing, on tumor growth. Bioinformatics of transcriptional data and immunopathology of PC samples were used to assess the translational value of the experimental findings.Human membrane-bound IL30 promoted PC cell proliferation, invasion and migration in association with STAT1/STAT3 phosphorylation, similarly to its murine, but secreted, counterpart. Both human and murine IL30 regulated PC driver and immunity genes and shared the upregulation of oncogenes, BCL2 and NFKB1, immunoregulatory mediators, IL1A, TNF, TLR4, PTGS2, PD-L1, STAT3, and chemokine receptors, CCR2, CCR4, CXCR5. In human PC cells, IL30 improved the release of IGF1 and CXCL5, which mediated, via autocrine loops, its potent proliferative effect. Deletion of IL30 dramatically downregulated BCL2, NFKB1, STAT3, IGF1 and CXCL5, whereas tumor suppressors, primarily SOCS3, were upregulated. Syngeneic and xenograft PC models demonstrated IL30's ability to boost cancer proliferation, vascularization and myeloid-derived cell infiltration, which were hindered, along with tumor growth and metastasis, by IL30 deletion, with improved host survival. RNA-Seq data from the PanCancer collection and immunohistochemistry of high-grade locally advanced PCs demonstrated an inverse association (chi-squared test, p = 0.0242) between IL30 and SOCS3 expression and a longer progression-free survival of patients with IL30NegSOCS3PosPC, when compared to patients with IL30PosSOCS3NegPC.Membrane-anchored IL30 expressed by human PC cells shares a tumor progression programs with its murine homolog and, via juxtacrine signals, steers a complex network of PC driver and immunity genes promoting prostate oncogenesis. The efficacy of CRISPR/Cas9-mediated targeting of IL30 in curbing PC progression paves the way for its clinical use.
Development of the “Teamwork in Endoscopy Assessment Module for Endoscopic Non-Technical Skills” (TEAM-ENTS) behavioral marker system
Authors: Srivathsan Ravindran, Rebecca Cavilla, Hutan Ashrafian, Adam Haycock, Chris Healey, Mark Coleman, Steph Archer, Ara Darzi, Siwan Thomas-Gibson
Journal: Endoscopy (2022)

Background Non-technical skills (NTS) are integral to team performance and subsequent quality and safety of care. Behavioral marker systems (BMSs) are now increasingly used in healthcare to support the training and assessment of team NTS. Within gastrointestinal endoscopy, this is an area of novel research. The aims of this study were to define the core relevant NTS for endoscopy teams and develop a preliminary framework for a team-based BMS known as TEAM-ENTS (Teamwork in Endoscopy Assessment Module for Endoscopic Non-Technical Skills). Methods This study was conducted in two phases. In phase 1, a literature review of team-based BMSs was performed to inform an interview study of core endoscopy team members. Cognitive task analysis was used to break down the NTS relevant to endoscopy teams. Framework analysis generated the structure for the preliminary TEAM-ENTS framework. In phase 2, a modified Delphi process was undertaken to refine the items of the framework. Results Seven consultant endoscopists and six nurses were interviewed. The final coding framework consisted of 88 codes grouped into five overarching categories. In total, 58 participants were recruited to the Delphi panel. In the first round, nine elements and 37 behavioral descriptors did not meet consensus. Following item adjustment, merging and deletion, all remaining items met consensus thresholds after the second round. The refined TEAM-ENTS BMS consists of five categories, 16 elements, and 47 behavioral descriptors. Conclusions The refined TEAM-ENTS behavioral marker system was developed to reflect the core NTS relevant to endoscopy teams. Future studies will aim to fully validate this tool.
Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control
Authors: Byron C. Jaeger, Adam P. Bress, Joshua D. Bundy, Alfred K. Cheung, William C. Cushman, Paul E. Drawz, Karen C. Johnson, Cora E. Lewis, Suzanne Oparil, Michael V. Rocco, Stephen R. Rapp, Mark A. Supiano, Paul K. Whelton, Jeff D. Williamson, Jackson T. Wright, David M. Reboussin, Nicholas M. Pajewski
Journal: JAMA Cardiology (2022)

The Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure control reduced cardiovascular morbidity and mortality. However, the legacy effect of intensive treatment is unknown.To evaluate the long-term effects of randomization to intensive treatment with the incidence of cardiovascular and all-cause mortality approximately 4.5 years after the trial ended.In this secondary analysis of a multicenter randomized clinical trial, randomization began on November 8, 2010, the trial intervention ended on August 20, 2015, and trial close-out visits occurred through July 2016. Patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke were included from 102 clinic sites in the US and Puerto Rico. Analyses were conducted between October 2021 and February 2022.Randomization to systolic blood pressure (SBP) goal of less than 120 mm Hg (intensive treatment group; n = 4678) vs less than 140 mm Hg (standard treatment group; n = 4683).Extended observational follow-up for mortality via the US National Death Index from 2016 through 2020. In a subset of 2944 trial participants, outpatient SBP from electronic health records during and after the trial were examined.Among 9361 randomized participants, the mean (SD) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a median (IQR) intervention period of 3.3 (2.9-3.9) years, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.01). However, at the median (IQR) total follow-up of 8.8 (8.3-9.3) years, there was no longer evidence of benefit for cardiovascular mortality (HR, 1.02; 95% CI, 0.84-1.24) or all-cause mortality (HR, 1.08; 95% CI, 0.94-1.23). In a subgroup of participants, the estimated mean outpatient SBP among participants randomized to intensive treatment increased from 132.8 mm Hg (95% CI, 132.0-133.7) at 5 years to 140.4 mm Hg (95% CI, 137.8-143.0) at 10 years following randomization.The beneficial effect of intensive treatment on cardiovascular and all-cause mortality did not persist after the trial. Given increasing outpatient SBP levels in participants randomized to intensive treatment following the trial, these results highlight the importance of consistent long-term management of hypertension.ClinicalTrials.gov Identifier: NCT01206062.
Association of Expanded Health Care Options for Community Care With Veterans’ Surgical Outcomes
Authors: Kamal M. F. Itani, Amy K. Rosen
Journal: JAMA Surgery (2022)

The implementation of the 2014 Veterans Choice (Choice) and 2018 MISSION acts expanded access to VA-purchased community care (CC) for eligible veterans. While access to CC has improved since Choice,1 little is known as to whether this legislation led to unintended consequences on quality of care.
Accuracy of Fine-Needle Aspiration for Cytologic Categorization of Thyroid Nodules—Incremental Progress vs Quantum Improvement
Authors: Alexis G. Antunez, Gerard M. Doherty
Journal: JAMA Surgery (2022)

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TP53 R249S mutation in hepatic organoids captures the predisposing cancer risk
Authors: Yin Kau Lam, Jianqing Yu, Hao Huang, Xiaofan Ding, Alissa M. Wong, Howard H. Leung, Anthony W. Chan, Kelvin K. Ng, Mingjing Xu, Xin Wang, Nathalie Wong
Journal: Hepatology (2022)

Background and Aims: Major genomic drivers of hepatocellular carcinoma (HCC) are nowadays well recognized, although models to establish their roles in human HCC initiation remain scarce. Here, we used human liver organoids in experimental systems to mimic the early stages of human liver carcinogenesis from the genetic lesions of TP53 loss and L3 loop R249S mutation. In addition, chromatin immunoprecipitation sequencing (ChIP‐seq) of HCC cell lines shed important functional insights into the initiation of HCC consequential to the loss of tumor‐suppressive function from TP53 deficiency and gain‐of‐function activities from mutant p53. Approach and Results: Human liver organoids were generated from surgical nontumor liver tissues. CRISPR knockout of TP53 in liver organoids consistently demonstrated tumor‐like morphological changes, increased in stemness and unrestricted in vitro propagation. To recapitulate TP53 status in human HCC, we overexpressed mutant R249S in TP53 knockout organoids. A spontaneous increase in tumorigenic potentials and bona fide HCC histology in xenotransplantations were observed. ChIP‐seq analysis of HCC cell lines underscored gain‐of‐function properties from L3 loop p53 mutants in chromatin remodeling and overcoming extrinsic stress. More importantly, direct transcriptional activation of PSMF1 by mutant R249S could increase organoid resistance to endoplasmic reticulum stress, which was readily abrogated by PSMF1 knockdown in rescue experiments. In a patient cohort of primary HCC tumors and genome‐edited liver organoids, quantitative polymerase chain reaction corroborated ChIP‐seq findings and verified preferential genes modulated by L3 mutants, especially those enriched by R249S. Conclusions: We showed differential tumorigenic effects from TP53 loss and L3 mutations, which together confer normal hepatocytes with early clonal advantages and prosurvival functions.
Initial implementation of HIV pre-exposure prophylaxis for people who are incarcerated in Zambia: a cross-sectional observational study
Authors: Brianna Lindsay, Nasho Nyirongo, Linah Mwango, Mona Gekanju Toeque, Carol Masumba, James Paul Litongola, James Sikanyika, Henry Kabombo, Martin Moyo, Steven Siachibila, James Mudenda, Kalima Tembo, Pawel Olowski, Adebayo Olufunso, Elizabeth Muchinda, Bupe Musonda, Jackson Okuku, Annie Mwila, Clement N Moonga, Michael E Herce, Cassidy W Claassen
Journal: The Lancet HIV (2022)